We propose to develop new general methods for the synthesis of the ophiobolin class of antibiotics, and in particular Ophiobolin C, by means of intramolecular cyclization procedures to form the key cyclooctane ring system. The ophiobolin class of antibiotics is a very diverse group of sesterterpenes--including the ceroplastols, cheilarinosin, fusicoccin, and cotylenol--with several members exhibiting antifungal, growth stimulant, phytotoxic and insecticidal activity. Our general synthetic route to these important molecules involves the construction of a bicyclo[3.3.0]octane template, either mono- or disubstituted, which could then be transformed into the desired perhydro dicyclopenta[a,d]cyclooctene ring system of the natural products by a simple cyclization process. The key methods for this cyclization reaction are: (1) a simple intramolecular alkylation of a keto tosylate; (2) intramolecular Michael addition, epoxide opening or aldol condensation; (3) internal C-acylation of a vinyl-silane with an acyl chloride; and (4) a McMurry reductive coupling-cyclization. The presence of the rigid bicyclo[3.3.0]octane system and several sp2 centers in the 8-membered ring which is being formed make these reactions favorable due to a great decrease in the torsional strain and transannular interactions in the transition state for cyclization. The key cyclization substrates are prepared in a relatively straightforward way from the readily available bicyclo[3.3.0]octane-3,7-dione and 8-alkyl bicyclo[3.3.0]octane-2-carboxylate. In this manner, we expect to prepare the natural ophiobolins and ceroplastols and their structural analogues in quantities large enough to permit biological testing. Agreements have been made with several commercial firms for such testing of all synthetic materials. Finally these methods could be applied to the synthesis of other medium-ring (8,9,10) natural products having biological activity.